Cystic fibrosis transmembrane conductance regulator (CFTR) maintains epithelial function by acting as an ion channel at the apical surface of epithelial cells, and governs the formation of mucus and its clearance. Genetic mutations of CFTR cause CF, and these mutations also contribute to other airway diseases by altering host defense. We have helped discover that CFTR dysfunction also can be acquired in the absence of congenital mutations, contributing to the pathogenesis of the chronic bronchitis phenotype of chronic obstructive pulmonary disease (COPD). To this aim, this Research Program will make decisive advancements in elucidating the pathogenesis of airway diseases linked to genetic and acquired CFTR dysfunction, and will apply this knowledge to develop new tools for their diagnosis and treatment. The Program will encompass two focus areas critical to the mission of the NHLBI. The first will tackle fundamental questions surrounding mucus clearance, using CF as the model. We will implement in vivo ?OCT imaging, a technique we co-invented that provides an unprecedented view of the functional microanatomy of the airway surface; perform innovative techniques to probe airway mucus; and use a novel CF rat that exhibits delayed mucus clearance and an inherit defect in host defense that develops over time to 1) illuminate mechanisms governing the formation of mucus and its clearance, 2) develop novel therapeutic approaches targeting abnormal mucus itself, and 3) establish mechanisms underlying increased susceptibility to chronic bacterial infection and novel strategies for bacterial eradication. In the second focus area, we will study the role of these pathways in chronic bronchitis, a prevalent disorder that lacks treatments that reverse its natural history. We will determine 1) the impact of acquired CFTR dysfunction in ferrets, the first animal model of chronic bronchitis, 2) mechanisms of mucus stasis in the human COPD airway (and contrast with CF), 3) whether acquired CFTR dysfunction increases susceptibility to chronic bacterial infection or respiratory exacerbations in COPD ferrets, and 4) test novel therapies for chronic bronchitis, including advancing CFTR potentiators for this indication. There will be significant synergy between these studies, which will not only employ cutting-edge techniques and animal models but also take advantage of our recognized expertise in leading first-in-class human investigation into CFTR-directed therapies. Noting Dr. Rowe's consistent track record of successes; the innovative, one-of-a-kind capabilities of his laboratory; and the immediate feasibility of proposed objectives, this Program promises to transform the field and uncover treatments that offer momentous improvements to duration and quality of life.